Doxorubicin is one of the most effective antitumor agents against hematological malignancies and certain human solid tumors such as breast carcinoma and osteosarcoma. However, its use is limited by acute myelosuppression, chronic cardiotoxicity, and natural or acquired drug resistance. In the last few years, there have been important advances in understanding the mechanisms of acquired resistance to doxorubicin and other structurally unrelated antitumor agents. Without being bound by any particular theory, it is now widely accepted that the overexpression of a membrane glycoprotein, P-glycoprotein, that acts as a drug efflux pump, mediates acquired resistance to doxorubicin in some in vitro systems and in vivo animal tumor models. It is also believed that overexpression of P-glycoprotein occurs in a significant number of cancer subjects when their tumors progress or relapse after treatment with doxorubicin. Despite the fact that 80% to 90% of patients with acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL) achieve a complete remission following intensive induction chemotherapy, more than 50% of patients relapse, often because recurrence of disease is associated with clinical drug resistance.
Since the introduction of doxorubicin in the current anticancer armamentarium, extensive efforts have been devoted to the synthesis of analogs with improved properties. Initially, most efforts were directed towards the preparation of analogs with reduced cardiotoxic potential. Those efforts have only been partially successful. More recently, and triggered by the discovery of the phenomenon of multidrug resistance and the identification of P-glycoprotein, the synthetic efforts have been more focused towards obtaining analogs with non-cross-resistance properties. Several non-cross resistant analogs have been identified. They all have in common a markedly increased lipophilicity. Some of them have a similar mechanism of cytotoxicity to that of doxorubicin i.e., topoisomerase II inhibition. Others have a different mechanism of action, i.e., DNA is alkylation
Liposomes have been used extensively as carriers of doxorubicin and daunorubicin. Liposomal-doxorubicin was reported as less cardiotoxic and more active than doxorubicin in models of liver metastasis in mice by several investigators. Several clinical studies have been conducted with different liposomal formulations of doxorubicin. These trials have shown an MTD similar to that of free doxorubicin, a significant reduction of certain toxicities, such as gastrointestinal and vesicant effects, and an unchanged dose-limiting toxicity, i.e., myelosuppression.
Surprisingly, Annamycin is an anthracycline antibiotic that has now been found to display a lack of cross-resistance properties and a very high affinity for lipid membranes. Annamycin is completely insoluble in water solutions. Liposomal Annamycin is useful as a carrier for intravenous annamycin administration. Some researchers in the field believe that a fundamental mechanism of action of Annamycin is inhibition of topoisomerase-II. L-Annamycin has shown lack of cross-resistance in vivo in KB/-VI human xenografts and enhanced antitumor activity compared with doxorubicin in several mouse tumor models in vivo. In mice, the dose-limiting toxicity of L-Annamycin is myelosuppression and its cardiotoxic potential less than that of doxorubicin. In dogs, the dose equivalent to the mouse LD10 was very well tolerated with no side effects, no blood chemical changes, and no pathological changes four weeks after drug administration.
The in vivo antitumor activity of L-Annamycin was tested in leukemia (L120), melanoma (B16), reticulosarcoma (m5076), and Lewis lung carcinoma cells. Results in KB and KB-V1 human xenografts demonstrate that L-Annamycin was at least as effective as doxorubicin, with the greatest antitumor activity against L1210 leukemia cells. It has been demonstrated that Annamycin is cytotoxic in MDR overexpressing HL-60 cells and that its resistance index is lower than that of idarubicin and doxorubicin.
The resistance index of Annamycin was found to be lower than that of idarubicin and doxorubicin. Coincubation in the presence of verapamil resulted in 4.5 fold and 2 fold resistance index decreases of doxorubicin and idarubicin, respectively, whereas Annamycin did not change. This suggests Annamycin's ability to circumvent p-gp mediated MDR. Unlike doxorubicin and idarubicin, Annamycin is not affected by p-gp mediated MDR.
The in vitro cytotoxicity of L-Annamycin was tested on a panel of four different parental MDR-1 expressing cell lines: the resistance index of L-Annamycin was significantly lower than that of doxorubicin, indicating that L-Annamycin is not cross-resistant with doxorubicin.
MDR-1 was identified as a major, independent negative prognostic factor in elderly patients with AML at diagnosis. In relapsed AML, a higher proportion of patients express MDR-1.
Anthracyclines are a class of antitumor agents. A particular class of anthracyclines are the 4-demethoxy-3′desamino-2′iodo analogs. This class is also described as compounds having the formula: where one of X and X′ is hydrogen and the other is halogen; one of Y and Y′ is hydrogen and the other is selected from the group consisting of hydrogen, hydroxy, and —OCOR; one of Z and Z′ is hydrogen and the other is selected from the group consisting of hydrogen, hydroxy, and —OCOR; where R is alkyl having approximately 1-6 carbon atoms.
In liposomal forms, these compositions are encapsulated in a liposome, and particularly where the liposome comprises at least one lipid and a nonionic surfactant, and where the weight ratio of the anthracycline compound to the nonionic surfactant is between approximately 0.5:1 and approximately 3:1.
Particular reference is made to (7S,9S)-4-demethoxy-7-O-(2,6-dideoxy-2-iodo-alphamannopryanosyl) adriamycinone (4-DMD) or annamycin having the formula
Annamycin is noteworthy as an anthracycline that is useful to overcome multidrug resistance (MDR), a response observed in many tumor cells. This is further illuminated in Blood, 88:633 (1996). In MDR, the tumor cell membrane glycoprotein, p-glycoprotein (p-gp), mediates resistance of doxorubicin, idarubicin, and mitoxantrone. Overexpression of p-gp is seen in a high percentage of patients with newly diagnosed refractory or relapsed leukemia.